ABSTRACT Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1% of individuals over the age of 60. There are currently no disease-modifying therapies that can slow the inevitable progression of PD. While aging is the greatest risk factor for the development of Parkinson's disease (PD), the role of aging in the pathogenesis of PD is not known. In the inherited forms of PD, the disease-causing mutation is present from birth and yet patients remain symptom free for decades. This suggests that the genetic defects that cause PD are well-tolerated in younger individuals. Based on this observation, we hypothesize that genetically- controlled changes that take place during normal aging make neurons more susceptible to genes and environmental factors that cause PD. This conclusion is supported by the fact that several changes that take place during the aging process have been implicated in the pathogenesis of PD. We further hypothesize that targeting molecular pathways that have been shown to modulate aging will provide an effective strategy for treating PD. To test this, we have conducted proof-of-principle studies using the powerful genetics of the worm C. elegans, which offers several advantages for the study of aging and neurodegenerative disease. We showed that decreasing insulin-IGF1 signaling through mutation of the insulin- IGF1 receptor gene daf-2 is neuroprotective in both ?-synuclein and LRRK2 models of PD. Importantly, the rescued neurons retained their function as decreasing insulin-IGF1 signaling also ameliorated deficits in dopamine-dependent behaviors. The objective of the current proposal is to extend these novel and exciting observations to genetic mouse models of PD to further establish whether targeting aging-related pathways can serve as a robust therapeutic target for PD. The long-term goal of this work is to define the contribution of aging to the pathogenesis of PD, and to use this information to develop treatments for this devastating disorder. The role of aging in PD will be elucidated through the completion of two Specific Aims: 1) To identify the specific molecular pathways, which have been shown to influence aging, that are most neuroprotective in the LRRK2 worm model of Parkinson's disease; 2) Determine the extent to which targeting aging pathways is beneficial in mouse models of PD. The expected outcome of this project is to determine the extent to which targeting aging pathways will be an effective treatment strategy for PD, and define the conditions that will result in maximum benefit. The significance of this work is that demonstrating that targeting aging pathways can ameliorate deficits in both worm and mouse models of PD would provide strong support that this strategy may also be effective in humans. This research is innovative in taking advantage of the most beneficial features of C. elegans and mouse models to directly test the effect of targeting aging pathways on PD pathogenesis. This work has the potential to improve human health through the identification of novel therapeutic targets for the treatment of PD.